Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB®.

The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed.

Biomimetic synthesis of the non-canonical PPAP natural products yezo'otogirin C and hypermogin D, and studies towards the synthesis of norascyronone A.

Oxidative degradation and rearrangement of polycyclic polyprenylated acylphloroglucinols (PPAPs) has created diverse families of unique natural products that are attractive targets for biomimetic synthesis. Herein, we report a racemic synthesis of hyperibrin A and its oxidative radical cyclization to give yezo'otogirin C, followed by epoxidation and House-Meinwald rearrangement to give hypermogin D. We also investigated the biomimetic synthesis of norascyronone A a similar radical cyclization pathway, with unexpected results that give insight into its biosynthesis.

Dissecting Programmed Cell Death with Small Molecules.

Programmed cell death (PCD) is fundamentally an indispensable process in all cellular activities, including cell development, wound healing, and immune surveillance of tumors (Galluzzi, L. et al. 2018, 25, 486-541).

Biomimetic Synthesis of Rhytidenone A and Mode of Action of Cytotoxic Rhytidenone F.

The rhytidenone family comprises spirobisnaphthalene natural products isolated from the mangrove endophytic fungus Rhytidhysteron rufulum AS21B. The biomimetic synthesis of rhytidenone A was achieved by a Michael reaction/aldol/lactonization cascade in a single step from the proposed biosynthetic precursor rhytidenone F. Moreover, the mode of action of the highly cytotoxic rhytidenone F was investigated.

Biomimetic and Biocatalytic Synthesis of Bruceol.

The first total synthesis of bruceol has been achieved using a biomimetic cascade cyclization initiated by a stereoselective Jacobsen-Katsuki epoxidation (and kinetic resolution) of racemic protobruceol-I. A bacterial cytochrome P450 monooxygenase was also found to catalyze the conversion of protobruceol-I into bruceol. The first full analysis of the NMR data of natural bruceol suggested that "isobruceol" was a previously unrecognized natural product also isolated from Philotheca brucei.

Biosynthetically-inspired oxidations of capillobenzopyranol.

The synthesis of verrubenzospirolactone from its proposed biosynthetic precursor, capillobenzopyranol, has been shown to be chemically feasible via a simple reaction sequence. The key steps are a chemoselective furan oxidation mediated by NaClO, a stereoselective dehydration of a γ-methoxybutenolide, and an intramolecular Diels-Alder reaction.

Biomimetic Total Synthesis of Rhodonoids C and D, and Murrayakonine D.

A divergent, three-step total synthesis of rhodonoids C and D has been achieved using a biosynthetically inspired, acid-catalyzed cascade cyclization of an epoxy-chromene that involves the presumed intermediacy of o-quinone methides. Application of a similar strategy also allowed synthesis of the alkaloid murrayakonine D.

Biomimetic Total Synthesis of (±)-Verrubenzospirolactone.

A five-step total synthesis of (±)-verrubenzospirolactone has been achieved using a biomimetic, intramolecular Diels-Alder reaction of a 2H-chromene to form two rings and four stereocenters in the final step. This Diels-Alder reaction occurs spontaneously at 30 °C "on-water", and thus suggests that it is likely to be non-enzymatic in nature. The structure of (±)-verrubenzospirolactone was also used to inspire a quadruple cascade reaction to generate seven stereocenters, four rings, three C-C bonds, and two C-O bonds in one step.

Biomimetic Total Synthesis of Hyperjapones A-E and Hyperjaponols A and C.

Hyperjapones A-E and hyperjaponols A-C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A-E using a biomimetic, oxidative hetero-Diels-Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid-catalyzed epoxide ring-opening; and 3) a concerted, asynchronous alkene cyclization and 1,2-alkyl shift of a tertiary carbocation.

Biomimetic total synthesis of (±)-yezo'otogirin A.

The total synthesis of yezo'otogirin A has been achieved via a biosynthetically-inspired strategy. Diastereoselective synthesis of pre-yezo'otogirin A, the proposed biosynthetic pre-cursor of yezo'otogirin A, was accomplished in eight steps from 3-ethoxy-2-cyclohexenone. A biomimetic oxidative radical cyclization was then used to construct the unique tricyclic ring system of yezo'otogirin A.

Biomimetic total synthesis of (±)-garcibracteatone.

The polycyclic polyprenylated acylphloroglucinol natural product garcibracteatone has been synthesized in four steps from phloroglucinol, using a strategy based on biosynthetic speculation. The key biomimetic transformation is a cascade of 7-endo-trig and 5-exo-trig radical cyclizations followed by a terminating aromatic substitution reaction.